Is FOXN1 p.Pro6= (c.18G>A) pathogenic?

FOXN1 p.Pro6= (c.18G>A) is classified Likely benign in FOXN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). Very rare (popmax 0.00223%, eas); Associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy.

What condition is associated with FOXN1 p.Pro6= (c.18G>A)?

FOXN1 p.Pro6= (c.18G>A) is associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy (ClinVar).

How common is FOXN1 p.Pro6= (c.18G>A) in the general population?

FOXN1 p.Pro6= (c.18G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

FOXN1 p.Pro6=

Q: How is Severe combined immunodeficiency due to FOXN1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.18G>A · rs184037357 · VCV2889810

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.47	GERP -2.9
Overall
CADD	13.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00174% 28/1,613,164 alleles · very rare exomes 24/1,460,938 · genomes 4/152,226 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
East Asiangrpmax	0.00223%	44,872
European (non-Finnish)	0.00203%	49,164
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00133%	75,004

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FOXN1
Protein: p.Pro6=
Coding: c.18G>A
MANE Select: NM_001369369
dbSNP: rs184037357
Type: single nucleotide variant
Location: chr17:28523987 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.44 · 2 PDB
Residue 6: the 'disordered' region

Full FOXN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

T-cell immunodeficiency, congenital alopecia, and nail dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to FOXN1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FOXN1 p.Pro6Leu Uncertain significance ★★ ⚠ same residue
FOXN1 p.Arg114Ter Pathogenic ★★★ same condition
FOXN1 p.Arg255Ter Pathogenic ★★★ same condition
FOXN1 p.Arg320Trp Pathogenic ★★★ same condition
FOXN1 p.Cys82Ter Pathogenic ★★★ same condition
FOXN1 p.Gln474Ter Pathogenic ★★★ same condition
FOXN1 p.His321Arg Likely pathogenic ★★★ same condition
FOXN1 p.Leu325Pro Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/foxn1-p-pro6 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown